research article open access tramadol for …background: tramadol is a centrally acting analgesic...

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RESEARCH ARTICLE Open Access

Tramadol for premature ejaculation: a systematicreview and meta-analysisMarrissa Martyn-St James1*, Katy Cooper1, Eva Kaltenthaler1, Kath Dickinson1, Anna Cantrell1, Kevan Wylie2,Leila Frodsham3 and Catherine Hood4

Abstract

Background: Tramadol is a centrally acting analgesic prescribed off-label for the treatment of premature ejaculation(PE). However, tramadol may cause addiction and difficulty in breathing and the beneficial effect of tramadol in PE isyet not supported by a high level of evidence. The purpose of this study was to systematically review the evidencefrom randomised controlled trials (RCT) for tramadol in the management of PE.

Methods: We searched bibliographic databases including MEDLINE to August 2014 for RCTs. The primary outcomewas intra-vaginal ejaculatory latency time (IELT). Methodological quality of RCTs was assessed. Between-groupdifferences in IELT and other outcomes were pooled across RCTs in a meta-analysis. Statistical and clinical between-trialheterogeneity was assessed.

Results: A total of eight RCTs that evaluated tramadol against a comparator were included. The majority of RCTs were ofunclear methodological quality due to limited reporting. Pooled evidence (four RCTs, 721 participants), suggests thattramadol is significantly more effective than placebo at increasing IELT over eight to 12 weeks (p = 0.0007). However, ahigh level of statistical heterogeneity is evident (I-squared = 74%). Single RCT evidence indicates that tramadol issignificantly more effective than paroxetine taken on-demand, sildenafil, lidocaine gel, or behavioural therapy on IELT inmen with PE. Tramadol is associated with significantly more adverse events including: erectile dysfunction, constipation,nausea, headache, somnolence, dry mouth, dizziness, pruritus, and vomiting, than placebo or behavioural therapy overeight to 12 weeks of treatment. However, addiction problems or breathing difficulties reported by patients for PE is notassessed in the current evidence base.

Conclusions: Tramadol appears effective in the treatment of PE. However, these findings should be interpreted withcaution given the observed levels of between-trial heterogeneity and the reporting quality of the available evidence.The variability across placebo-controlled trials in terms of the tramadol dose evaluated and the treatment duration doesnot permit any assessment of a safe and effective minimum daily dose. The long-term effects and side effects, includingaddiction potential, for men with PE have not been evaluated in the current evidence base.

Trial registration: The review is registered on PROSPERO 2013:CRD42013005289.

Keywords: Premature ejaculation, Tramadol, Systematic review, Meta-analysis, Efficacy, Safety

BackgroundPremature ejaculation (PE) is commonly defined by ashort ejaculatory latency, a perceived lack of ejaculatorycontrol; both related to self-efficacy; and distress andinterpersonal difficulty [1]. PE can be either lifelong(primary), present since first sexual experiences, or

* Correspondence: [email protected] for Health and Related Research (ScHARR), University of Sheffield,Regent Court, 30 Regent Street, Sheffield S1 4DA, UKFull list of author information is available at the end of the article

© 2015 Martyn-St James et al.; licensee BioMeCreative Commons Attribution License (http:/distribution, and reproduction in any mediumDomain Dedication waiver (http://creativecomarticle, unless otherwise stated.

acquired (secondary), beginning later [2]. The recentlyupdated International Society of Sexual Medicine’sGuidelines for the Diagnosis and Treatment of Prema-ture Ejaculation (PE) propose that PE is a male sexualdysfunction characterised by ejaculation within aboutone minute of vaginal penetration (lifelong PE) or a re-duction in latency time to ≤3 minutes (secondary PE),the inability to delay ejaculation, and negative personalconsequences [3].

d Central. This is an Open Access article distributed under the terms of the/creativecommons.org/licenses/by/4.0), which permits unrestricted use,, provided the original work is properly credited. The Creative Commons Publicmons.org/publicdomain/zero/1.0/) applies to the data made available in this

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The treatment of PE should attempt to alleviateconcern about the condition as well as increase sexualsatisfaction for the patient and the partner [4]. Availabletreatment pathways for the condition are varied andtreatments may include both behavioural and/or phar-macological interventions. Tramadol is a centrallyacting analgesic agent that combines opioid receptoractivation and re-uptake inhibition of serotonin andnoradrenaline, prescribed off-label for the treatment ofPE. Dapoxetine (a selective serotonin re-uptake inhibitor)is currently the only approved oral drug to treat PE. InMay 2009, the US Food and Drug Administration re-leased a warning letter about tramadol's potential tocause addiction and difficulty in breathing [5]. Tramadolhas previously been evaluated by three systematic re-views [6-8], two of which have pooled data in a meta-analysis [7,8]. The search methodology and inclusioncriteria vary across these reviews. Of the two reviews in-cluding a meta-analysis, one [7] pooled data across dif-ferent study types (observational studies and RCTs)using a mean difference [7]. One review pooled IELT ef-fect estimates across studies using a standardised meandifference [8]. The European Association of Urologyguidelines for the management of PE summarise thattramadol has shown a moderate beneficial effect with asimilar efficacy as dapoxetine. However, that the benefi-cial effect of tramadol in PE is yet not supported by ahigh level of evidence [9].The aim of this study was to systematically review the

evidence base for tramadol in the management of PE,by summarising evidence from randomised controlledtrials (RCTs) and reporting a mean difference meta-analysis of RCT IELT data. The review addressed thequestion “in men with premature ejaculation, what isthe clinical effectiveness of tramadol as comparedwith a non-active comparators or other treatments,evaluated in randomised controlled trials”. The reviewis registered on PROSPERO 2013:CRD42013005289.Available from http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42013005289.

MethodsThe review was undertaken in accordance with the ge-neral principles recommended in the Preferred Repor-ting Items for Systematic Reviews and Meta-Analyses(PRISMA) statement [10].

SearchesThe following databases were searched from inceptionto 5 August 2014 for published and unpublished re-search evidence: MEDLINE; Embase; Cumulative Indexto Nursing and Allied Health Literature (CINAHL); TheCochrane Library including the Cochrane SystematicReviews Database (CDSR), Cochrane Controlled Trials

Register (CCRT), Database of Abstracts of Reviews ofEffects (DARE) and the Health Technology Assessment(HTA) database; ISI Web of Science (WoS), includingScience Citation Index, and the Conference ProceedingsCitation Index-Science. Full search terms are reportedelsewhere [11]. The U.S. Food and Drug Administration(FDA) website and the European Medicines Agency(EMA) website were also searched. Existing systematicreviews were also checked for eligible studies. Allcitations were imported into Reference Manager Soft-ware and any duplicates deleted. The MEDLINE searchstrategy is presented as an Additional file 1.

Study selectionSearches were screened for potentially relevant studiesby one reviewer and a subset checked by a second re-viewer (and a check for consistency undertaken). Fulltexts were screened by two reviewers. Details of studiesidentified for inclusion were extracted using a data ex-traction sheet.

Eligible studiesRCTs in adult men with PE that evaluated tramadolwere eligible for inclusion. Randomised crossover de-sign studies were excluded to avoid double counting ofparticipants in the meta-analysis. Theses and disserta-tions were not included. Non-English publications wereincluded where sufficient data could be extracted froman English-language abstract or tables.

OutcomesThe primary outcome was intra-vaginal ejaculatorylatency time (IELT). Other outcomes included sexualsatisfaction, control over ejaculation, relationship satis-faction, self-esteem, quality of life, treatment accept-ability and adverse events.

Data extractionOne reviewer performed data extraction of each in-cluded study. All numerical data were then checked by asecond reviewer.

Methodological quality of studiesMethodological quality of RCTs was assessed using theCochrane Collaboration risk of bias assessment criteria[12]. We classified RCTs as being at overall ‘low’ or‘high’ risk of bias if they were rated as such for each ofthree key domains - allocation concealment, blinding ofoutcome assessment and completeness of outcome data(attrition <30%).

Data synthesisWhere possible, between-group differences for directcomparisons (e.g., tramadol vs. placebo) were pooled




across trials in a pairwise meta-analysis using CochraneRevMan software (version 5.2) (RevMan 2012 [13]).Continous variables were analysed as a mean difference(MD) and dichotomous variables as a risk ratio (RR).No subgroup or sensitivity analyses were planned. Forcomparisons where there was little apparent clinicalheterogeneity and the I2 value (I2 statistic [14]) was 40%or less, a fixed-effect model was applied. Random-effects models were applied where I2 value was >40%.Between-group effect estimates were considered sig-nificant at p < 0.05. Where >5 RCT comparisons wereavailable, publication bias was assessed by visual in-spection of funnel plots.

Ethical approval and consent from patientsThe project was not primary research involving humansor animals but was a secondary analysis of human sub-ject data available in the public domain.

Records identifiedthrough database

searching(n=2,331

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enin

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clud

ed

Elig

ibili

ty

Iden

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Records screened –title and/or abstract

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for eligibilityn=12)

Full text articles assessed

8 RCTs included in the evidence s

Figure 1 Study selection process - Preferred Reporting Items for Syst

ResultsSearch resultsThe searches identified 2,331 citations (as part of a widerproject assessing a variety of treatments for PE [11]). Ofthese, 2,319 citations were excluded as titles/abstracts.Twelve full-text articles were obtained as potentiallyrelevant. The study selection process is fully detailed inthe PRISMA flow diagram in Figure 1. A total of sevenRCTs that evaluated tramadol against a comparator(placebo, another agent, or behavioural therapy) and oneRCT that evaluated different tramadol doses (eight RCTsin total) were identified.Details of the included RCTs, the comparator(s),

outcomes assessed and the risk of bias assessment aredetailed in Table 1.

Risk of bias assessment of RCTsThe majority of RCTs were considered at overall unclearrisk of bias mainly due to lack of reporting of information

Additional recordsidentified through

other sources(n=0)

Records excluded attitle/abstract stage:

Not relevant (n=2,319)

Full text articles excluded, withreasons (n=4):Review of SRRIs (n=3)Crossover tramadol trials (n=1)

ynthesis

ematic Reviews and Meta-Analyses (PRISMA) flow diagram.

Table 1 RCT characteristics, efficacy and safety outcomes, and risk of bias assessment

RCT(country)duration

PE definition,Lifelong/acquired PE,erectiledysfuntion

Treatment, comparator, numbersanalysed/randomised (%) When taken

Efficacy outcomes and results Adverse events Risk of bias assessment

Alghobary2010 [15](Egypt)6 weeks

DSM-IV-TR Alllifelong PEED, NR

- Tramadol 50 mg 2 to 3 h PC, 17/17(100%) - Paroxetine 20 mg/d, 18/18(100%)

IELT (Stopwatch): see Figure 3. Arabic Indexof Premature Ejaculation (AIPE): significantimprovement in scores at 6 weeks with bothtramadol and paroxetine. Difference betweengroups not significant. Tramadol group hadless rigid erections than paroxetine group

The drugs were generally toleratedand no serious side-effects encounteredapart from mild headache and gastricupset with paroxetine and mainly gastricupset with tramadol and no withdrawncases recorded.

Unclear risk - allocationmethod and blindedoutcome assessmentnot reported

Bar-Or2012 [18](11 EUcountries)12 weeks

DSM-IV-TR Alllifelong PE ED,excluded

- Tramadol 62 mg, 206/232 (89%) -Tramadol 89 mg, 198/217 (91%) -Placebo, 200/228 (88%) 2 to 8 h PC

IELT (Stopwatch): see Figure 3. PrematureEjaculation Profile (PEP): Mean change for all4 measures significantly higher in bothtramadol groups than placebo Femalepartner PEP scores: more had improvement(> = 1 category) for tramadol than placeboon all 4 measures

Any adverse event: Tramadol 62mg: 12% Tramadol 89 mg: 16% Placebo:7% No difference was observed in theincidence of withdrawal by treatmentgroup (0.0% placebo, 1.0% 62 mgtramadol, 1.6% 89 mg tramadol). Therewere no serious AEs.


Eassa 2013[20] (Egypt)24 weeks

PE def, NR Alllifelong PEED, excluded

- Tramadol 25 mg, 100/100 (100%) -Tramadol 50 mg, 100/100 (100%) -Tramadol 100 mg, 100/100 (100%)2 to 3 h PC

IELT (Stopwatch): see Figure 3 Tramadol 25 mg - somnolence (100%);pruritus (100%) Tramadol 50 mg -somnolence (100%); pruritus (100%);dizziness (18%); headache (16%); drymouth (13%) Tramadol 100 mg -somnolence (100%); pruritus (100%);dizziness (38%); headache (30%); drymouth (20%); nausea (20%); vomiting(17%)


Gameel2013 [16](Egypt)4 weeks

IELT of <2 minin >75% ofepisodes All hadPE for >1 yearED, excluded

- Tramadol 50 mg 2 h PC + inertlubricating gel 15 min PC, 29/30 (97%) -Sildenafil 50 mg 1 h PC + inert lubricatinggel 15 min PC, 30/30 (100%) - Paroxetine20 mg 4 h PC + inert lubricating gel15 min PC, 28/30 (93%) - Lidocaine gel15 min PC + oral multivitamin 1-4 h PC,30/30 (100%) - Placebo (oral multivitamin1-4 h PC + inert lubricating gel 15 minPC), 27/30 (90%)

IELT (stopwatch): see Figure 3. Sexualsatisfaction (0 to 5 point scale: Tramadol andparoxetine were associated with comparabledrug-induced improvements in sexualsatisfaction, but tramadol was associated withsignificantly better sexual satisfaction scoresthan was the local anaesthetic.

Greater sleep disturbance, dry mouth,nausea, dizziness, fatigue, vomiting,sweating, and headache were reportedwith tramadol, sildenafil and paroxetine.All side effects were reported as beingtolerable.


Kahn 2013[21] (India)8 weeks

DSM-IV TR41/60 (68%)lifelong PEED, excluded

- Tramadol 100 mg/d, 4 weeks then 2 or8 h PC, 4 weeks; 30/30 (100%) - Placebo/d, 4 weeks then 2 or 8 h PC, 4 weeks;30/30 (100%)

IELT (stopwatch): Week 8 tramadol daily 202.5 s,2 or 8 h PC, 238.2 s (p < 0.001 vs baseline);placebo daily 94.8 s (p = 0.632 vs baseline)placebo 2 or 8 h PC 96.6 s (p = 0.611 vsbaseline). Coital frequency tramadol daily4.32/week (p = 0.005) tramadol 2 or 8 h PC4.86/week (p = 0.005). Coital frequency placebodaily 2.88/week (p = 0.875) placebo 2 or 8 hPC 3.23/week (p = 0.752).

The overall AE rate was 9.8% (6.7%, and12.4% for placebo and 100 mg tramadolrespectively) ED occurred in 3.33% ofmen (n = 1). Vertigo was observed in3.33% of patients (n = 2); dizziness,headache, drowsiness, and commoncold were observed in 6.67% of patients(n = 2 each). There were no serious AEs.


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Table 1 RCT characteristics, efficacy and safety outcomes, and risk of bias assessment (Continued)

Kaynar2012 [17](Turkey)8 weeks

IELT ≤2 minduring 90%intercourseepisodes Alllifelong PE ED,excluded

- Tramadol 25 mg, 30/30 (100%) -Placebo, 30/30 (100%) 2 h PC

IELT (stopwatch): see Figure 3. Ability ofejaculation control (AEC): Tramadol: Meanincrease 2.0 Placebo: Mean increase 0.57Tramadol better than placebo (p < 0.001)Sexual satisfaction scores (SSS) Tramadol:Mean increase 1.80 (SD 0.98). Placebo: Meanincrease 0.53 (SD 0.92) Tramadol better thanplacebo (p < 0.001)

Any adverse event: Tramadol: 27%Placebo: 0% Mild nausea/headache:Tramadol: 20% Mild somnolence:Tramadol: (6.5%)

Unclear risk - allocationmethod and blindedoutcome assessment notreported

Safarinejad2006 [19](Iran)8 weeks

IELT ≤2 minduring 90%coitus All lifelongPE ED, excluded

- Tramadol 50 mg, 29/32 (91%) -Placebo, 28/32 (88%) 2 h PC

IELT (stopwatch): see Figure 3. IIEF: intercoursesatisfaction: Tramadol: mean change 4 Placebo:mean change −1 Between-groups p < 0.05

Any adverse event: Tramadol: 28%Placebo: 16% (mainly nausea)

Unclear risk - blindedoutcome assessmentnot reported

Xiong 2011[22] (China)12 weeks

IELT ≤2 min Alllifelong PE ED, NR

- Tramadol 50 mg 2 h PC with behaviouraltherapy (not reported which) (n = 36) -Behavioural therapy alone (n = 36);

IELT (stopwatch): see Figure 3. IIEF Tramadol +BT: mean change 4 BT alone: mean change 2Between-groups p < 0.05

Any adverse event: Tramadol: 28%Placebo: 0% Tramadol: nausea (11.1%),vomiting (2.8%), dry mouth (5.6%),dizziness (8.3%).

Unclear risk - allocationmethod and blindedoutcome assessment notreported (unable to assessfully – body text of articlein Chinese)

/d, daily; DSM, Diagnostic and Statistical Manual of Mental Disorders; ED, erectile dysfunction; IELT, intra-vaginal ejaculatory latency time; IIEF, International Index of Erectile Dysfunction; NR, not reported; PC, pre-coitus;PE, premature ejaculation.

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to inform the risk of bias assessment. Three RCTs weredescribed as single-blind and were considered at high riskof performance bias [15-17]. One RCT was considered tobe at overall high risk of bias as randomisation to studygroups was according to patients’ presentation sequenceat clinic, suggesting a non-random component in the se-quence generation [17]. A summary of the risk of bias as-sessment for each included RCT is presented in Figure 2.

Characteristics of RCTsRCT details of the treatments, efficacy and safety out-comes, and the risk of bias assessment are presented inTable 1. Where reported, the definition of PE was variedand was defined according to: DSM-IV (Diagnostic andStatistical Manual of Mental Disorders) criteria [15,18],an IELT of two minutes or less [16,17,19], or was not re-ported [20]. The majority of RCTs recruited samples

Figure 2 Risk of bias assessment summary by RCT.

comprising men with lifelong PE and without erectiledysfunction.Tramadol was prescribed across all RCTs, on-demand

one to four hours prior to sexual intercourse. Prescribeddoses varied and range from 25 mg [17,20] to 100 mg[20,21]. Comparators included placebo [17-19,21], se-lective serotonin re-uptake inhibitors (SSRI) [15,16],phosphodiesterase-5 (PDE5) inhibitors [16], anaestheticgel [16] and behavioural therapy [22]. One RCT evalu-ated three tramadol doses only (no placebo) [20]. Treat-ment duration ranged from four weeks to six months.The majority of included RCTs were 8 weeks duration.Only one trial was undertaken in the EU (across 11 EUcountries) [18]. The remainder were undertaken inEgypt [15,16,20], Turkey [17], India [21], Iran [19] andChina [22].

Outcome data reported by RCTsIELT was assessed by all of the included RCTs (Table 1,Figure 3, Figure 4). Where reported, the assessmentmethod was by stopwatch. The reporting of other efficacyoutcomes was much more varied, both in the assessmentmethod and the outcome data available (Table 1). Acrossthe majority of RCTs, outcome data for adverse eventreporting was disparate in terms of limited reporting oftypes of adverse events and patient numbers.

Data synthesisIELT as a mean outcome with a variance estimate wasavailable for all but two RCTs [21,23]. One reported sig-nificant changes in IELT at week eight in the tramadolgroup (p < 0.001) [23]. P-values for the between-groupdifference compared with placebo, or the change in theplacebo group, were not reported. One RCT reportedsignificant changes in IELT at week eight with tramadoldaily (p < 0.001) or on-demand (p < 0.001), but not pla-cebo (p = 0.632 and 0.611). P-values for the between-group difference were not reported.Tramadol vs. placebo: Meta-analysis of mean IELT

change (minutes) at 8 or 12 week follow-up, basedon -four RCT study group comparisons from -threeRCTs (n = 721), displayed high heterogeneity (I2 = 74%).The pooled mean difference (MD) in IELT was 1.24 mi-nutes, favouring tramadol [MD (random effects) 95%confidence interval [CI], 0.52 to 1.95; p = 0.009]. Thebetween-group difference in end of study values at fourweeks based on one RCT (n = 56) was 4.50 minutes (95%CI 3.75 to 5.25; p < 0.00001), in favour of tramadol. Theforest plot for these analyses is presented in Figure 2.Significant improvements on measures of the Premature

Ejaculation Profile (PEP) (p < 0.05 for all) with tramadolcompared with placebo were reported by one RCT [18]Significant between-group differences on the International

Figure 3 Tramadol vs. comparator - forest plot of IELT outcomes.


Index of Erectile Function (IIEF) mean number of coitusper week and mean intercourse satisfaction favouringtramadol (p < 0.05) were reported by one RCT [19] A sta-tistically significant increase in weekly coitus associatedwith tramadol daily (p = 0.005) or on-demand (p = 0.005)was reported by one RCT (p-values for placebo p = 0.875and 0.752 respectively) [21]. One RCT reported significantimprovements on ability of ejaculation control and sexualsatisfaction scores (instrument not reported) for tramadolover placebo (p < 0.001 for both) [17]. One RCT reported asignificant between-group difference of p < 0.05 on the IIEFintercourse satisfaction score in favour of tramadol [17].Where reported, adverse events associated with trama-

dol included: erectile dysfunction, constipation, nausea,

headache, somnolence, dry mouth, dizziness, pruritus(itching), and vomiting. Meta-analysis of numbers ex-periencing adverse events at 8 or 12 week follow-up dis-played low heterogeneity (I2 = 0%). The pooled relativerisk (RR) across five RCTs (583 participants) was 2.27[RR (fixed effect) 95% confidence interval [CI], 1.45 to3.57; p = 0.0004] in favour of placebo (lower risk). Theforest plot for this analysis is presented in Figure 4.Tramadol vs. paroxetine (SSRI): The between-group

difference in geometric mean IELT (minutes) at 6 weeks,based on one RCT (n = 70) comparing tramadol withparoxetine taken daily, was −0.83 [95% CI, −1.80 to 0.14;p = 0.09]. The between-group difference in end of studymean IELT (minutes) at four weeks based on one RCT

Figure 4 Tramadol vs. comparator - forest plot for adverse events.


(n = 57) was 2.74 (95% CI 1.91 to 3.57); p < 0.00001, infavour of tramadol compared with paroxetine taken on-demand (Figure 2).One RCT [15] reported that paroxetine daily improved

the Arabic Index of Premature Ejaculation score at6 weeks (p < 0.05) and 12 weeks (p < 0.05) whereas tram-adol improved AIPE at 6 weeks but not at 12 weeks.One RCT reported that both tramadol and paroxetineon-demand were associated with comparable improve-ments in sexual satisfaction (p > 0.05) [16].One RCT reported that mild headache and gastric

upset were associated with paroxetine daily and mainlygastric upset with tramadol [15] One RCT reported thatsleep disturbance, dry mouth, nausea, dizziness, fatigue,vomiting, sweating, and headache were reported withtramadol, sildenafil and paroxetine on-demand, but thatall side effects were tolerable [16].Tramadol vs. sildenafil (PDE5 inhibitor): The between-

group difference in end of study mean IELT (minutes) atfour weeks based on one RCT (n = 59) was 2.01 (95% CI1.21 to 2.87); p < 0.00001, in favour of tramadol (Figure 2).Tramadol with behavioural therapy vs. behavioural

therapy alone: The between-group difference in meanIELT (minutes) at 12 weeks, based on one RCT (n = 72),was 1.65, significantly favouring tramadol combined withbehavioural therapy [95% CI, 0.30 to 3.00; p = 0.02]. Theforest plot for this analysis is presented in Figure 2. Thesame RCT reported a between-group difference at8 weeks of P < 0.05 on the International Index of ErectileFunction (IIEF) favouring the tramadol group [22]. Thebetween-group difference in numbers of participants ex-periencing adverse events at 12 weeks was 21.00 [RR(random effects) 95% confidence interval [CI], 1.28 to

345.410; p = 0.03] in favour of behavioural therapy alone(lower risk). The forest plot for this analysis is presentedin Figure 4.Tramadol vs. lidocaine gel: The between-group diffe-

rence in end of study mean IELT (minutes) at fourweeks based on one RCT (n = 59) was 1.21 (95% CI 0.23to 2.17); p = 0.02, in favour of tramadol (Figure 2). Thesame RCT reported that tramadol was associated withsignificantly better sexual satisfaction scores than wasthe local anaesthetic (p < 0.05) [16].Tramadol 25 mg, 50 mg, or 100 mg: One RCT (n = 300)

evaluated three different doses of tramadol. The between-group differences in mean IELT (minutes) at 24 weekswere: 10.65 in favour of tramadol 50 mg vs. 25 mg [95%CI, 9.76 to 10.76; p < 0.00001]; 23.32 in favour of tramadol100 mg vs. 25 mg [95% CI, 22.59 to 24.05; p < 0.00001];and 13.06 in favour of tramadol 100 mg vs. 50 mg [95%CI, 12.33 to 13.79; p < 0.00001]. The forest plot for thisanalysis is presented in Figure 5. The same RCT [20], re-ported that all patients in the trial experienced one ormore adverse events (all experienced somnolence andpruritus).

DiscussionPooled evidence across four RCT study groups (721 par-ticipants), suggests that tramadol is significantly moreeffective than placebo at increasing IELT over eight to12 weeks. However, a high level of between-trial statis-tical heterogeneity is evident. The largest between-groupeffect size (3.52 min) was notable for one RCT [19].Three clinical studies by the same investigator have beenretracted in the past three years. However, excluding thisRCT from the analysis did not significantly alter the

Figure 5 Tramadol different doses - forest plot of IELT outcomes.


overall effect size (1.02 min) or reduce the between-trialheterogeneity (I-squared = 71%).The placebo-controlled RCTs prescribed tramadol

doses from 25 mg to 89 mg. Reporting of the methodo-logical quality across these RCTs was limited. Blindedoutcome assessment was not reported by any of theRCTs, which may have contributed to detection bias.Allocation concealment was not reported by five ofRCTs, which may have contributed to selection bias[16-18,20-22]. One of the RCTs randomised participantsaccording to their presentation sequence at clinic, whichmay have also contributed to selection bias [17]. Assuch, these results should be interpreted with caution.The evidence from one RCT (70 participants) suggests

that there is no difference in IELT between tramadol takentwo to three hours prior to sexual intercourse and paroxe-tine daily [15]. Conversely, evidence from another RCT(59 participants) indicates that tramadol is significantlymore effective than paroxetine taken on-demand at in-creasing IELT [16]. However, concealment of allocationand blinded outcome assessment were not reported by ei-ther RCT, and treatment duration was relatively short (sixand four weeks respectively). As such, these results shouldbe interpreted with caution. One of these RCTs also didnot include a placebo group comparison [15]. Commonlyused SSRIs in the management of PE including paroxetine(20 to 40 mg/d), are prescribed daily [9]. SSRIs such asparoxetine are absorbed slowly [24]. The half-lives of flu-oxetine, paroxetine and sertraline range from 16 to96 hours [25]. The pharmacokinetic properties of paroxe-tine may also account for the diverse results for the effectsof tramadol compared with paroxetine on IELT.Single RCT evidence also suggests that tramadol is sig-

nificantly more effective than sildenafil, lidocaine gel, or

behavioural therapy on IELT in men with PE. However,reporting of the methodological quality is limited interms of concealment of group allocation and blindingof the outcome assessment across all RCTs included bythis review.Various assessment methods in terms of ejaculation

control, patient/partners sexual satisfaction, anxiety andother patient-reported outcomes have been used acrossRCTs to measure the effectiveness of tramadol. Acrossplacebo-controlled RCTs, tramadol was reported assignificantly more effective than placebo for variouspatient-reported outcomes. Pooled evidence across trials(817 participants) suggests that tramadol is associatedwith significantly more adverse events including: erectiledysfunction, constipation, nausea, headache, somno-lence, dry mouth, dizziness, pruritus (itching), and vo-miting, than placebo or behavioural therapy over eightto 12 weeks of treatment. Addiction to tramadol by pa-tients treated with tramadol for PE was not assessed inthe current evidence base. Likewise, patient acceptabilityof treatment was not reported. However, one RCT re-ported 100% follow-up of all patients prescribed 25 mg,50 mg or 100 mg of tramadol over 24 weeks [20]. Allparticipants at all doses (100%) reported somnolence.The trial was considered of unclear methodologicalquality.With the exception of one RCT [18], all of the in-

cluded RCTs were conduction in non-EU countries, fivebeing conducted in Middle East and Arab State coun-tries [15-17,19,20]. In a population-based stopwatchstudy, Waldinger et al. [26] observed the largest diffe-rence in IELT observed between Turkey and partici-pants from the United Kingdom and the United States.Because characteristics of PE may differ culturally, the


observations from this review might not be gene-ralizable across men from EU countries.The risk of bias assessment indicates the majority of

RCTs of tramadol in the treatment of PE are of unclearrisk of detection bias, mainly due to limited reporting re-garding blinding of the outcome assessment. Key aspectsof best practice in RCT design to minimise bias includea robust randomisation method, concealment of treat-ment group allocation, and, where possible, blinding ofparticipants and trial personnel, and blinded outcomeassessment; all of which should be clearly stated in theRCT report [27].Although our database search strategy was compre-

hensive, the possibility of a publication bias cannot bediscounted. Insufficient numbers of RCT comparisonswere available for any meaningful assessment of funnelplot symmetry to be undertaken. Nonetheless, althoughthe RCTs identified for inclusion were of unclear meth-odological quality, it could be considered unlikely thatany additional unpublished data for the effects of trama-dol compared with placebo would contribute signifi-cantly to the overall findings of this review.The RCTs evaluating tramadol identified for inclusion

evaluated treatments over four to 12 weeks and none re-ported a long-term follow-up on efficacy and safety out-comes, including addiction potential. However, moreimportant is a requirement for clearer evaluations of therelationship between treatment-related increases in IELT,ejaculatory control and sexual satisfaction associatedwith tramadol. Adverse event data suggest that tramadolis associated with a number of adverse events, but thatthese appear tolerable. However, the long-term use oftramadol for the treatment of PE in terms of a safetyprofile including addiction potential is unclear from thecurrent evidence base.The results observed by this review for the effective-

ness of tramadol in treatment of PE are comparable withother reviews [6-8]. However, where meta-analyses havepreviously been undertaken, methodological errors areevident [7,8]. This review has pooled data across RCTs,where appropriate, in a meta-analysis using a mean dif-ference to summarise IELT outcomes and has avoideddouble-counting of participants in the analysis.The European Association of Urology 2014 Guidelines

on male sexual dysfunction recommend that pharmaco-logical treatment options include ‘on demand’ dapoxe-tine, daily use of a longer acting selective serotoninreuptake inhibitor (SSRI) [off-label use], daily use of clo-mipramine (off-label use), ‘on demand’ topical local an-aesthetic agents (off-label use) and ‘on demand’ tramadol(off-label use) [9]. Given that tramadol has been exten-sively evaluated against placebo for the treatment of PE inthe current evidence base, with limited head-to-headcomparisons between tramadol and other treatments

(paroxetine, sildenafil and lidocaine gel), further directcomparisons between tramadol and other SSRIs includ-ing dapoxetine, other PDE5 inhibitors, and other top-ical anaesthetics should now be investigated. Whilst theobserved increases in IELT were statistically significantin favour of tramadol, it is difficult to quantify how ac-ceptable and meaningful these changes are for menwith PE, without being able to evaluate the relationshipbetween IELT, ejaculation control, and sexual satisfac-tion from the current RCT evidence base for tramadol.The trade-off between IELT and other effectiveness out-comes versus adverse effects and addiction potentialshould also be further evaluated.

ConclusionTramadol appears more effective than placebo or behav-ioural therapy in the treatment of PE. However, thesefindings should be interpreted with caution given theobserved levels of between-study heterogeneity and themethodological quality of the available evidence.

Additional file

Additional file 1: MEDLINE search strategy.

AbbreviationsDSM: Diagnostic and Statistical Manual of Mental Disorders; EU: EuropeanUnion; IIEF: International Index of Erectile Function; IELT: Intra-vaginalejaculatory latency time; PDE5: Phosphodiesterase-5; PE: Prematureejaculation; RCT: Randomised controlled trial; SSRI: Selective serotoninreuptake inhibitor.

Competing interestsThe authors declare that they have no competing interests.

Authors’ contributionsMMSJ and KC selected studies for inclusion and undertook qualityassessment and data extraction. MMSJ undertook the meta-analysis anddrafted the manuscript. KC, EK, KW, LF and CH commented on themanuscript. All authors read and approved the final manuscript.

AcknowledgementsKC and AC designed the search strategy and ran the electronic searches forthe project. KW, LF and CH acted as clinical advisors.

FundingThis work was funded by NIHR Evaluation, Trials and Studies CoordinatingCentre (NETSCC).The views and opinions expressed therein are those of the authors and donot necessarily reflect those of the Health Technology AssessmentProgramme, NIHR, NHS or the Department of Health.

Author details1School for Health and Related Research (ScHARR), University of Sheffield,Regent Court, 30 Regent Street, Sheffield S1 4DA, UK. 2Porterbrook Clinic,Sexual Medicine, Sheffield, UK. 3Institute of Psychosexual Medicine, London,UK. 4St George’s Hospital, London, UK.

Received: 14 August 2014 Accepted: 26 January 2015Published: 30 January 2015

http://www.biomedcentral.com/content/supplementary/1471-2490-15-6-S1.docx


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doi:10.1186/1471-2490-15-6Cite this article as: Martyn-St James et al.: Tramadol for prematureejaculation: a systematic review and meta-analysis. BMC Urology2015 15:6.

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